The presentation discusses about Carcinoid and pancreatic neuro endocrine tumor, the disease, diagnosis, treatment options in various stages.

1. CARCINOID and PANCREATIC
NEUROENDOCRINE TUMORS
PRESENTED BY: ALOK GUPTA

2. History
1890- Ranson, first description of a
carcinoid(Ileum).
1907- Oberndorfer, used the term ‘karzinoide’.
1928- Masson stated that carcinoids should be
considered as endocrine tumors.
1953- Lembech demonstrated the presence of
serotonin in carcinoid tumors.
1955- Page et al. described increased urinary 5-
HIAA in patients with carcinoid syndrome.

3. Modlin IM, Oberg K, Chung DC et al. Gastroenteropancreatic neuroendocrine
tumours. Lancet Oncol 2008; 9: 61–72

4. Epidemiology
SEER- the estimated annual incidence of
carcinoid tumors in 2004 was 5.25 per
100,000 population and slightly more
common in females (55% of all cases).
The incidence in England, Scotland, Spain, Italy,
and Japan is 0.7 per 100 000 people.
In autopsies, however, the rate tends to be
much higher. (0.65%- 1.2%)

5. Nomenclature and Classification of
Neuroendocrine Tumors
Evolving process:
• 1907- Oberndorfer, used the term ‘karzinoide’.
• 1963- Williams & Sandler(location)
• 1980- The first WHO classification of NETs
• 2000–2004- WHO updated classification based on
histopathology.
• 2006 and 2007- ENETs TNM system based on the WHO
system. ENETS also proposed three tumor grades
based on mitotic count and proliferative index (Ki-67).
• 2009- International Union Against Cancer/ American
Joint Committee on Cancer published a new TNM
classification system

8. Carcinoid Incidence by Location
Location % of Patients
Foregut Thymus 0.4%
Lung, bronchi, trachea 29.8%
Stomach 4.9%
Midgut Small intestine 30.4%
Gallbladder, pancreas 1%
Appendix 5.1%
Hindgut Colon 9.2%
Rectum 14.5%
Adapted from Modlin IM, Lye KD, Kidd M. A 5-decade analysis of
13,715 carcinoid tumors. Cancer. 2003;97:934-959.

9. Pathology
The neuroendocrine cell system:
1. Glands
2. DNES(lung, gastrointestinal tract, skin,
thyroid, thymus, pancreas, biliary, and
urogenital tracts)
Carcinoid tumors are characterized by
monotonous sheets of small round cells with
uniform nuclei and cytoplasm.

10. (a) Microscopic section from a well-
differentiated neuroendocrine carcinoma
demonstrating low mitotic rate and low-
grade bland histology.
(b) Microscopic section from a poorly
differentiated neuroendocrine carcinoma
demonstrating high mitotic rate and high-
grade histology similar in appearance to small
cell carcinomas.

11. Well differentiated NET
A. Carcinoids:
1. Gastrointestinal carcinoids(75%)
2. Non-Gastrointestinal carcinoids(25%)
B. Pancreatic NET
1. Gastrinoma, 60% malignant, 90% multiple, 30%-
MENI, majority in duodenum
2. Insulinoma, 10% malignant, 80% active
3. Glucagonoma, usually malignant, 4D
4. VIPoma, Somatostatinoma, Ppoma.

12. Gastrointestinal carcinoids
A. Gastric carcinoids:
• 75% a/w chronic atrophic gastritis type A
• 5-10% a/w gastrinoma and the familial MEN1
• 15-25% sporadic cases
B. Intestinal carcinoids:
• Midgut carcinoid- mc type of carcinoid,
frequently presents with intestinal obstruction,
abdominal pain, diarrhea, and gastrointestinal
bleeding. 90% cases of carcinoid syndrome.

13. Symptoms
• Endocrinologically inactive(50-70%) Appendicitis,
bowel obstruction, painful hepatomegaly.
Bronchial carcinoids produce cough, hemoptysis,
frequent pulmonary infection.
• Endocrinologically active(30-50%)- carcinoid
syndrome- Attacks of flushing, diarrhea,
hypotension, light-headedness, bronchospasm
either spontaneous or precipitated by emotional
or physical stress, alcohol, vigorous liver
palpation.
Heart failure, chronic skin changes

14. neuron-specific enolase,
5-hydroxytryptophan(5-HTP),
synaptophysin,
chromogranin-A and C,
growth hormone,
neurotensin,
pancreatic polypeptide,
calcitonin,
tachykinins,
growth hormone-releasing hormone,
bombesin,
adrenocorticotropic hormone
(ACTH),
kallikrein,
glucagon,
histamine,
catecholamines,
prostaglandins,
substance P,
gastrin,
insulin,
pancreastatin,
And various growth factors
such as transforming
growth factor
(TGF-), platelet-derived
growth factor (PDGF), and
bfibroblast growth factor
Carcinoid tumors produce and secrete a number of
substances, including

15. Carcinoid Syndrome

16. 99% 1%
Niacin
5-HIAA
5-HT
Dietary
Tryptophan
99% 1%
Pellegra- Triad: dermatitis, diarrhea, dementia

17. Symptoms cont..
• Specific to the type of pancreatic
neuroendocrine tumor:
1. Gastrinoma- severe peptic ulcer disease with
diarrhea.
2. Insulinoma- fasting hypoglycemia
3. Glucagonoma- dermatosis, diarrhea,
depression and deep vein thrombosis.
4. VIPoma- Watery diarrhea, hypokalemia,
achlorhydria.

18. Diagnosis
• Routine blood- CBC, RFT, LFT, FBS, SE
• Abdominal USG/CT scan
• Chest CT
• Upper GI endoscopy
• Nuclear imaging using radiolabelled somatostatin analog-
Octreoscan(80-90% sensitive), Lu177 DOTATOC
• Biopsy
• Symptomatic pts- 5-HIAA( 24 hours urinary level>9mg),
CgA(non-specific)
• Others- Fasting serum gastrin level(>500 pg/ml),
insulin(>6µU/ml + hypoglycemia), C peptide.
• Individuals with sporadic or familial bronchial or gastric
carcinoid should have a family history evaluation and
consideration of testing for germline MEN1 mutations.

19. Radiopharmaceuticals used in imaging
NETs
(68)Ga-DOTATOC PET is superior to (111)In-DTPAOC SPECT in the detection of
NET manifestations in the lung and skeleton and similar for the detection of
NET manifestations in the liver and brain
-Buchmann I et al, Eur J Nucl Med Mol Imaging. 2007 Oct;34(10):1617-26. Epub
2007 May 23.

20. Sensitivities (%) of various imaging techniques
Ramage JK, Davies AH, Ardill J et al. Guidelines for the management of
gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut
2005; 54 (Suppl 4): iv1–iv16.

23. Prognostic factors for NET
• A primary tumour of >2.5 cm
• Presence of clinical symptoms
• Ki67 index
• Any oncological surgical procedure was associated with a decreased
risk of death.
• Presence of metastasis at initial diagnosis is a risk factor for first
tumour progression.
-Ulrich-Frank Pape et al,Prognostic factors of long-term outcome in
gastroenteropancreatic neuroendocrine tumours. Endocrine-Related
Cancer (2008) 15 1083–1097

24. In patients with midgut carcinoids:
• multiple liver metastases,
• presence of carcinoid syndrome,
• advanced age and
• plasma chromogranin A >5000 μg/l were
independent predictors of overall survival.
- Janson ET et al,Carcinoid tumors: Analysis of prognostic factors and survival
in 301 patients from a referral center. Annals of
Oncology.1997, vol. 8, no7, pp. 685-690.

25. Treatment
• Principle- Therapeutic restraint
• Octreotide- ameliorates symptoms in 90%.
• Hypotension- Methoxamine, norepinephrine
• Flushing- H1 and H2 blockers, prednisolone
• Bronchospasm- aminophylline
• Diarrhea- loperamide, diphenoxylate,
methysergide, ondansetron

26. Treatment
Locoregional disease: Resection of the primary tumor and
local lymph nodes is the treatment of choice. Adjuvant
therapy for carcinoid tumors is not recommended.
• Localized pulmonary carcinoid tumors, a wedge or
segmental resection is preferred.
• Gastric carcinoids- <1cm local excision,>2cm subtotal
gastrectomy.
• S I carcinoid- resection that includes lymphadenectomy
and removal of the mesentery.
• Carcinoids of the appendix-< 2 cm appendectomy,
>2cm right hemicolectomy.

27. Treatment of Advanced Disease
1. Treatment of Patients with Hepatic-
predominant Metastatic Disease
2. Somatostatin Analogs
3. Peptide receptor radionuclide therapy (PRRT)
4. Interferon Alpha
5. Cytotoxic Chemotherapy
6. Molecular Targeted Therapy

28. Treatment of Patients with Hepatic-
predominant Metastatic Disease
• In selected cases, metastatic liver disease can be
surgically resected.
• The role of transplantation in this setting remains
uncertain.
• Hepatic arterial embolization
1. Bland (gelatin powder, polyvinyl alcohol)
2. Chemo (fluorouracil/doxorubicin/CDDP/mitomycin C)
3. Radioembolization- yttrium (90Y) microspheres
Tumor response rate:
For Bland and chemo embolization: 33% to 60%
For Radioembolization: 63%

29. Somatostatin Analogs
• SSTRs are highly expressed on NETs(5 subtypes- SSTR1–5)
• Somatostatin inhibits the release of pituitary hormones and
GI hormones (e.g., insulin, gastrin, and serotonin), inhibits
flushing, diarrhea, and other symptoms of carcinoid
syndrome.
• It also has antiproliferative, proapoptotic, and anti-
angiogenic activity.
• Analogs:
1. Octreotide: 2 forms, an aquaeous, immediate-release product
and long-acting release (LAR) form.
2. Lanreotide and Lanreotide Autogel(new).
3. Pasireotide is a panreceptor agonist that binds SSTR1–3 and
SSTR5 with high affinity

30. Response Rate to somatostatin analogs
A randomized study of lanreotide sustained release compared with
octreotide in 33 patients with carcinoid syndrome demonstrated similar
rates of symptom control. O’Toole D, Ducreux M, Bommelaer G, et al. Treatment of
carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide
in terms of efficacy, patient acceptability, and tolerance. Cancer. 2000;88:770- 776.

31. • Octreotide LAR significantly lengthened time
to tumor progression compared with placebo
(14.3 and 6 months, respectively; p 0.000072)
in midgut carcinoids.(independent of
functionality, CgA level, PS or age).
• Rinke A, Mu¨ ller H, Schade-Brittinger C, et al. Placebo-controlled, double blind,
prospective, randomized study on the effect of octreotide LAR in the control of
tumor growth in patients with metastatic neuroendocrine midgut tumors: a report
from the PROMID study group. J Clin Oncol. 2009;27:4656-4663.

32. ‘Escape from response’ phenomenon:
Role of pasireotide
• After 6–18 months, mechanism unknown
• Pasireotide -high affinity for sst1–3 and sst5
• In a phase II trial of patients with refractory
carcinoid syndrome treated with pasireotide,
symptom control was achieved in 12 (27%) of
44 patients. Kvols L, Wiedenmann B, Oberg K, et al. Safety and efficacy of
pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or
resistant to octreotide LAR: results of a phase II study. J Clin Oncol 2006;24:18s (suppl;
abstr 4082).
• A phase III study of pasireotide LAR versus octreotide LAR is
ongoing

33. Peptide receptor radionuclide therapy
(PRRT)
• The most frequently used radionuclides for targeted radiotherapy include
90Y and 177Lu.
• Complete and partial tumor remissions with [177Lu-
DOTA0,Tyr3]Octreotate: occurred in 2% and 28% of 310 GEPNET patients.
Median time to progression was 40 months and median OS was 46
months. Compared with historical controls, there was a survival benefit of
40 to 72 months from diagnosis.
- Dik J. Kwekkeboom et al. Treatment With the Radiolabeled Somatostatin Analog
[177Lu-DOTA0,Tyr3]Octreotate: Toxicity, Efficacy, and Survival. J Clin Oncol 26:2124-2130.
• 90Y-edotreotide was evaluated in a prospective, phase II study of 90
patients with metastatic carcinoid tumors. The objective tumor response
rate was 4%, although more than 50% of patients experienced
improvement in symptom control.

35. Interferon Alpha
• Mechanism: IFN-alpha 2a and IFN-alpha 2b bind to
specific IFN receptors on NET cells, potentially leading
to changes in gene transcription, inhibition of protein
synthesis, and degradation of peptide hormones.
• Have a biochemical response in at least 30% to 35% of
patients. Oberg KE. Gastrointestinal neuroendocrine tumors. Ann Oncol. 2010;
21:vii72-vii80 (suppl 7).
• One prospective randomized trial of octreotide with or
without IFN-alpha in patients with progressive
metastatic foregut and midgut NETs has reported no
substantial differences in time to treatment failure and
long-term survival between treatment arms. Arnold R, Rinke
A, Klose K, et al. Octreotide versus octreotide plus interferon-alpha in endocrine
gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol.
2005;3:761-771

36. • The role of IFN in the treatment of carcinoid
remains controversial. When used, it is typically
after a trial of SSTAs, in the setting of
unresectable, progressive metastases, alone or in
combination with octreotide.
• Currently, IFN is being compared with
bevacizumab in a large randomized study
performed by the Southwest Oncology Group
(SWOG) and the North American Intergroup
(S0518).

37. Cytotoxic Chemotherapy
Carcinoid
1. Streptozocin/fluorouracil (FU)
2. Doxorubicin/FU
• The radiographic response rate was similar for the two
regimens (16% each), and there was a slight but statistically
significant median survival benefit associated with
streptozocin/FU (24 vs. 16 months).Sun W, Lipsitz S, Catalano P, et al. Phase II/III
study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the
treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol.
2005;23:4897-4904.
3. Temozolomide-based regimens, only one patient (2%)
experienced a tumor response. Kulke M, Hornick J, Frauenhoffer C, et al. O6-
methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in
patients with neuroendocrine tumors. Clin Cancer Res. 2009;15:338-345.
With relatively modest response rates they are currently rarely
used in this setting.

38. Pancreatic NETs
• In contrast to carcinoid tumors, pancreatic NETs are clearly
responsive to cytotoxic chemotherapy.
STREPTOZOCIN BASED:
• Treatment with streptozocin and doxorubicin was associated
with combined biochemical and radiologic response rate of
69% and a median survival duration of 2.2 years. Moertel CG,
Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or
chlorozotocin in the treatment of advanced isletcell carcinoma. N Engl J Med.
1992;326:519-523

39. TEMOZOLOMIDE BASED:
In phase II studies in pancreatic NET, temozolomide has been
combined with thalidomide, bevacizumab, or everolimus, with
overall response rates ranging from 24% to 45%.
•Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in
patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24:401-406.
•Kulke M, Stuart K, Earle C, et al. A phase II study of temozolomide and bevacizumab in patients
with advanced neuroendocrine tumors. J Clin Oncol. 2006;24:18s (suppl; abstr 4044).
•Kulke M, Blaszkowsky L, Zhu A, et al. Phase I/II study of everolimus (RAD001) in combination
with temozolomide (TMZ) in patients (pts) with advanced pancreatic neuroendocrine tumors
(NET). 2010 Gastrointestinal Cancers Symposium:Abstract 2010;127.
Temozolomide combined with capecitabine- objective response
rate was 70%.
Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide
in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2010;117:268-275.

40. Molecular Targeted Therapy
• Inhibitors of the vascular endothelial growth
factor (VEGF) signaling pathway and the
mammalian target of rapamycin (mTOR) have
demonstrated activity in patients with NETs.
• These agents appear to be more active in
pancreatic than in carcinoid NETs.

41. Vascular Endothelial Growth Factor
Pathway Inhibitors
• VEGF expression correlates with angiogenesis,
metastases, and decreased PFS among
patients with low-grade NET.
• Agents under investigation/approved:
– the anti-VEGF antibody bevacizumab,
– VEGFR tyrosine kinase inhibitors (TKIs), including
sunitinib, sorafenib, and pazopanib.

42. TKI in Carcinoid NETs.
• Sunitinib, sorafenib, and pazopanib have been
evaluated in the phase II setting.
– low radiographic response rates (2.4%)
– relatively high rate of disease stabilization(83%)
– encouraging PFS duration (6-months PFS, 40% to
73% across studies).
• Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitnib in patients with advanced
neuroendocrine tumors. J Clin Oncol. 2008;26:3403-3410.
• Hobday TJ, Rubin J, Holen K, et al. MC044h, a phase II trial of sorafenib in patients (pts) with
metastatic neuroendocrine tumors (NET): a phase II consortium (P2C) study. J Clin Oncol.
2007;25:18s (suppl; abstr 4505).
• Phan A, Yao J, Fogelman D, et al. A prospective, multi-institutional phase II study of
GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade
neuroendocrine carcinoma (LGNEC). J Clin Oncol, 2010;28:18s (suppl; abstr 4044).

43. Bevacizumab in Carcinoid NETs.
• Phase II study of 44 patients, patients were randomly
assigned to 18 weeks of bevacizumab or pegylated IFN
alpha 2b, followed by treatment with both drugs.
• Results: During the first 18 weeks of therapy,
– four (18%) of the bevacizumab-treated patients
experienced radiographic partial responses,
– 95% of patients treated with octreotide plus bevacizumab
remained progression free, compared with only 68% of
those receiving octreotide plus IFN alpha 2b.
• On the basis of these results, SWOG is leading a large,
randomized study of bevacizumab compared with
interferon in patients with advanced carcinoid tumors
(S0518).

44. TKI in Pancreatic NETs.
• In an initial phase II trial, sunitinib (50 mg daily
for 4 of every 6 weeks) was administered to
109 patients with advanced NETs.
• Result: Of 61 patients with pancreatic NETs, 11
(18%) had a partial response.
– Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitnib in patients with advanced
neuroendocrine tumors. J Clin Oncol. 2008;26:3403-3410.

45. 171 patients were randomly assigned to receive sunitinib at a dose of 37.5 mg per day
or placebo. The primary end point was PFS.
Agent No. of
Patients
Tumor
Response
Rate (%)
Median TTP
or PFS
(Months)
Sunitinib 86 9 11.4
Placebo 85 0 5.5
(hazard ratio [HR] 0.42; p 0.001).

46. • Two other tyrosine kinase inhibitors, sorafenib
and pazopanib, have been evaluated in phase
II study.
Sorafenib -responses were observed in 11%
Hobday TJ, Rubin J, Holen K, et al. MC044h, a phase II trial of sorafenib in
patients (pts) with metastatic neuroendocrine tumors (NET): a phase II
consortium (P2C) study. J Clin Oncol. 2007;25:18s (suppl; abstr 4505).
Pazopanib-The response rate among patients
with pancreatic NETs was 17%.
Phan A, Yao J, Fogelman D, et al. A prospective, multi-institutional phase II study of
GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade
neuroendocrine carcinoma (LGNEC). J Clin Oncol, 2010;28:18s (suppl; abstr 4044).

47. mTOR Pathway Inhibitors
CARCINOID
• Phase II study of Everolimus+octreotide- Partial
responses were observed 17% patients.
• Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in
advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J
Clin Oncol. 2008;26:4311-4318.
• Phase III study- 429 patients were randomly assigned
to receive everolimus plus octreotide LAR, or placebo
plus octreotide LAR. Although this analysis also favored
the everolimus arm over placebo (PFS- 16.4 vs. 11.3
months; HR 0.77, p 0.026), the predefined threshold
for statistical significance (p 0.0246) was not met.
• Yao JC, Hainsworth JD, Baulin E., et al. Everolimus plus octreotide LAR (EO) versus placebo
plus octreotide LAR (P) in patients with advanced neuroendocrine tumors (NET): updated
results of a randomized, double-blind, placebo-controlled, multicenter phase III trial
(RADIANT-2). J Clin Oncol. 2011;29:4 (suppl; abstr 159).

48. mTOR Pathway Inhibitors in Pancreatic
NETs.
• Phase II study- octreotide + everolimus, 27%
of patients experienced partial responses.
• Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide
LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a
phase II study. J Clin Oncol. 2008;26:4311-4318.

49. Agent No. of
Patients
Tumor
Response
Rate (%)
Median TTP
or PFS
(Months)
Everolimus 207 NR 11
Placebo 203 NR 4.6
Everolimus was associated with a significant prolongation in median PFS
(11.6 vs. 4.6 months; HR 0.35, log-rank p 0.0001).
James C. Yao,et al
(RADIANT-3)

50. Combination Regimens with Molecularly
Targeted Therapies
• Everolimus and bevacizumab was recently shown
to be well tolerated and associated with an
overall response rate of 26% in a phase II single-
arm study enrolling patients with low- or
intermediate-grade NETs.
• Combination of temozolomide and everolimus in
patients with pancreatic NET reported objective
response rate of 35%.
• The combination of everolimus with pasireotide
is also well-tolerated and potentially active.

51. Studies from India
• Amarapurkar DN, et al. A retrospective clinico-
pathological analysis of neuroendocrine tumors
of the gastrointestinal tract. Trop Gastroenterol
2010 Apr-Jun;31(2):101-4.
• Results:74 patients, male preponderance(2.5:1),
stomach 22 (30.2%), followed by pancreas 17
(23.3%) and duodenum 14 (18.9%), 3 (4.1%)
patients presented with carcinoid syndrome,
disease was localized in 46.

52. Summary
• The clinical course of patients with metastatic NETs is highly
variable.
• Patients with symptoms of hormone hypersecretion will, in
most cases, achieve symptomatic improvement with
somatostatin analogs.
• Advanced Carcinoid- Treatment with SSTAs has been shown
to improve PFS. IFN or cytotoxic agents are sometimes used
in the second-line setting. mTOR and VEGF pathway
inhibitors have shown activity in carcinoid but the precise
role of these agents has not yet been established.
• Advanced pancreatic NETs- Treatment with either
everolimus or sunitinib has recently been shown to prolong
PFS. Treatment with streptozocin- or temozolomide-based
regimens will likely also continue to play a role particularly
in those with a high tumor burden.

53. THANK YOU